Biomarker Discovery Methods Evolving

Protein Phosphorylation States

The clinical significance of certain proteins’ phosphorylation state is well-established; for instance, persistent tyrosine phosphorylation in the transcription factor STAT3 is observed in a variety of tumors. As for autoantibodies and glycomics, though, tools for large-scale investigation of phosphorylation biomarkers are just starting to emerge.

One firm working in this area is Evotec. The company’s PhosphoScout® platform permits identification and quantification of thousands of cellular phosphorylation events.

“In contrast to other technologies, PhosphoScout does not require phosphate-specific antibodies,” explained CSO Cord Dohrmann, Ph.D. “The detection of phosphate groups is based on masses in the mass spec; we can therefore comprehensively detect phosphorylation on tyrosine, serine, and threonine residues.”

For a given sample, “The phosphorylation status of up to 10,000 to 15,000 individual phosphorylation sites can be measured separately with high accuracy and reproducibility,” Dr. Dohrmann noted.

Evotec currently offers its phosphoproteome analysis as a service to clients, but it is also pursuing discovery research in which phosphoproteome signatures may be identified as possible biomarkers. Along these lines, a PhosphoScout analysis of the effects of the cancer drug sorafenib, a protein kinase inhibitor, suggests that this drug may inhibit the mTOR pathway in prostate cancer cells.

Hypothesis-Free Sequence Discovery

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According to Genomic Expression, its hypothesis-free biomarker platform abbreviates the process and takes out most of the uncertainty. The diagnostic becomes a bioinformatics exercise that allows the drug discovery company to optimize its definition of the responder group based on the available signals rather than making expensive guesses.

These days, looking for biomarkers among genetic mutations and mRNA transcripts is not especially novel in and of itself. But Genomic Expression is developing technology to make this analysis faster, cheaper, and less biased.

The heart of Genomic Expression’s technology is the creation of a single-stranded library of nucleic acid tags of defined length from double-stranded DNA or cDNA, followed by decoding of all possible sequences in the library on a GEx Digital Chip. Since all possible sequences are decoded, no assumptions need to be made about which ones will be informative—i.e., biomarker discovery can proceed in a hypothesis-free fashion—and even samples of unknown sequence (e.g., from microbiome samples) can be analyzed.

As new cancer drugs are developed, companies must come up with a biomarker strategy that will guide usage of the drugs, explained CEO Gitte Pedersen. “We can assist them in doing that without having to hypothesize around the target or the mechanisms—or the mechanisms for nonresponders,” she said.

The current version of the GEx Digital Chip can be read by existing array-scanning equipment to which many labs have access. It therefore generates data quickly and in a compact, accessible format, whereas methods such as RNA-Seq require both next-generation sequencing and extensive bioinformatics analysis to obtain interpretable data, Pedersen noted.

Biomarker Grants

Bayer Healthcare’s Grants4Targets program was launched in 2009 as a way of bringing new participants and ideas into the drug discovery pipeline, especially in areas like cardiology, oncology, and gynecology, reported Khusru Asadullah, M.D., who serves as head of global biomarkers at Bayer. About a year ago, the program was broadened to include biomarkers explicitly.

This reflected the program’s initial success as a catalyst for drug discovery research, Bayer’s interest in the field of biomarkers, and the fact that some early applications concerned molecules that could conceivably represent both drug targets and biomarkers. Applications written purely from a biomarker perspective are now receiving funding, and Dr. Asadullah anticipates seeing many more of these proposals in the future.

While applications from all sources are permitted, the program is designed especially “to provide something of a door-opener for academic groups that may not have experience collaborating with big pharma,” Dr. Asadullah said.

Unusual features of the Grants4Targets program include the simple application, fast review process (about eight weeks from submission to decision), lack of intellectual property restrictions, and partnering of grant recipients with specific Bayer scientists.

According to Dr. Asadullah, many grant recipients consider the access to industry resources at least as valuable as the grant money itself. “We provide to every project an internal Bayer scientist as a kind of caretaker,” he said, “and we are trying to support the projects by giving advice, and sometimes even by providing data and running some experiments and applying technologies that might not be available at the academic site.”

Overall, the Grants4Targets has received about 600 applications to date and made 77 awards. While it is too early to expect many success stories from the biomarker side, one drug target project has already progressed to lead optimization at Bayer, and another is at the lead-generation stage.

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